State and situation of avian influenza in the Eastern Mediterranean Region

Abstract Avian influenza viruses have had a significant burden of disease on animal and public health in countries of the Eastern Mediterranean Region. In this review, we aimed at describing the state of avian influenza in the region from 2011 to 2021. We gathered information available through the peer‐reviewed scientific literature, public gene sequence depositories, OIE World Animal Health Information System platform, World Health Organization FluNet, Joint External Evaluation reports, and governmental, Food and Agriculture Organization of the United Nations, and World Organization for Animal Health websites. We used an interdisciplinary perspective consistent with the One Health approach to perform a qualitative synthesis and making recommendations. Analysis showed that although avian influenza research in the Eastern Mediterranean Region has gained more attention during the last decade, it was limited to only few countries and to basic science research. Data highlighted the weakness in surveillance systems and reporting platforms causing underestimation of the actual burden of disease among humans and animals. Inter‐sectoral communication and collaboration for avian influenza prevention, detection, and response remain weak. Influenza surveillance at the human‐animal interface and the application of the One Health paradigm are lacking. Countries' animal health and public health sectors rarely publish their surveillance data and findings. This review suggested that surveillance at the human‐animal interface, research, and reporting capacities should be enhanced to improve understanding and control of avian influenza in the region. Implementing a rapid and comprehensive One Health approach for zoonotic influenza in the Eastern Mediterranean Region is recommended.


| INTRODUCTION
Avian influenza (AI) viruses cause devastating outbreaks in poultry with severe economic consequences due to high mortality in birds and significant drop in egg production. 1 Based on pathogenicity, AI viruses are classified into highly pathogenic avian influenza (HPAI) viruses that cause severe disease in poultry and result in high death rates and low pathogenic avian influenza (LPAI) viruses that cause mild disease in poultry. 2 Eastern Mediterranean Region (EMR) countries lie under four of the eight global migratory bird flyways 3 : Central Asia-India, West Asia-Africa, Mediterranean-Black Sea, and East Atlantic. This opens the door to the transmission of AI viruses from migratory birds to the resident wild birds, domestic poultry, mammalian species, and humans.
Since 2003, H5N1 spread has been responsible for millions of poultry infections and several human outbreaks and deaths in many countries in Asia, Europe, the Middle East, and Africa, 4 and has become endemic in poultry populations in some countries (Bangladesh, China, Egypt, India, Indonesia, and Vietnam). 5 H5N1 AI has spread rapidly through the EMR in 2006 with large epizootics reported in Iraq, Egypt, Jordan, Palestine, Afghanistan, Pakistan, Djibouti, and Sudan. 6 The burden became more significant in the EMR when transmission of H5N1 from infected birds to humans was con-  7 all of whom were exposed to sick or dead poultry. Egypt, where the disease remains endemic, has reported the most cases in the EMR, with a total of 359 reported human cases and 120 deaths (33.4% CFR). 7 Since its emergence and spread in some EMR countries, the H5N1 virus has evolved resulting in a range of circulating clades. Avian influenza viruses of the H9N2 subtype are widely circulating in avian species causing severe economic losses. H9N2 is endemic in poultry of many EMR countries and has been reported in Lebanon, Jordan, Egypt, Tunisia, Saudi Arabia, and the UAE. 13 Therefore, avianto-human transmission becomes an important public health concern as H9N2 viruses have the ability to cross the species barrier and infect humans. 14 The apparent adaptation of avian H9N2 virus to mammalian cells is in agreement with the WHO's alertness for a possible public health threat. Sero-epidemiologic studies from different EMR countries documented evidence of H9N2 antibodies in exposed humans. 15 Few cases of infection to humans were reported from Egypt. H9N2 viruses are likely enzootic in all EMR countries 16,17 and have undergoing genetic evolution due to transmission, including vaccinations, 18 as H9N2 vaccines are used in some EMR countries such as Egypt, Lebanon, and Jordan. Within country, evolution, and emergence of reassortants and new subclades were reported. 19 We conducted this systematic review to describe the state and situation of avian influenza in the EMR over the period 2011-2021.

| Search strategy
We used PubMed to search the peer-reviewed literature using the search terms "Avian Influenza" and "country name" ( Figure S1). Countries of the EMR region include Afghanistan, Bahrain, Djibouti, Egypt, Iran, Iraq, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Pakistan, Palestine, Qatar, Saudi Arabia, Somalia, Sudan, Syria, Tunisia, United Arab Emirates (UAE), and Yemen.

| Eligibility criteria
The included publications met the following eligibility criteria: (1) publications report avian influenza research in one or more EMR countries; (2) publications are published in the period from 2011 to 2021; (3) publications are assigned to one of the following categories: virology, editorial, epidemiology, epizootiology, health care management, modeling, reporting, review, surveillance. Publications were excluded for the following reasons: (1) duplicates, (2) records not related to avian influenza research in the EMR.

| Data extraction
Publications from PubMed search were exported to Endnote X8 library. Duplicates were removed. Retained publications were exported to an excel spreadsheet for abstract revision. Records not related to avian influenza research in the EMR were excluded. The following data were extracted from each included study: publication year, country, and category. Comparing human case reports with available serological studies reveals that current surveillance systems are not reflecting the true incidence and burden of disease. 4 For instance, data from a cohort study of Egyptian poultry growers conducted between 2015 and 2019 revealed that 11% of poultry growers had neutralizing antibodies against H9N2 and negligible seroprevalence of H5N1. 15 This finding is in line with a previous study suggesting that the public health surveillance systems are only detecting severe cases of HPAI infections that are admitted to hospitals. 21 Further research indicated that human infections with HPAI and LPAI viruses may be mild to moderate with symptoms resembling seasonal influenza viruses supporting the notion that surveillance systems as they stand tend to miss those infections. 22 Research indicates that the cause of human infections with AI viruses is exposure to sick or dead domestic poultry. 23 However, the true routes of transmission were not studied.  (Table 1). Out of the 22 EMR countries, 11 (50%) did not report any AI virus outbreak in animals from 2011 to 2021, three (13.6%) countries reported less than 10. These modest numbers could be an underestimation of the actual burden of disease. Updating surveillance programs and reporting systems should be considered to reflect the real AI virus transmission among poultry. Almost all the outbreaks were reported in domestic poultry, out of which 15% were HPAI and 85% were LPAI which is most likely due to H9N2 ( Figure S2).

| Avian influenza A(H5N1) virus infections in humans
In the EMR, not all countries report AI surveillance data. Between     Figure S7), endemic in reporting countries, and of HA and NA proteins ( Figure S8).

| Zoonotic influenza surveillance platforms in the Eastern Mediterranean Region
In countries with better surveillance capacities, AI surveillance is  Egypt  226  102  342  505  138  357  116  53  307  15  1  2162   Iraq  0  0  1  0  0  0  0  0  10  0  0  11   Iran  12  59  57  6  0  0  0  and response in the veterinary and/or public health sectors, absence of multisectoral sharing of surveillance data, absence of joint surveillance systems between the animal and public health sectors, and absence of formal structures or framework to facilitate and sustain multisectoral collaboration.

| DISCUSSION
EMR countries must remain vigilant and aware of the threat of HPAI H5Nx viruses as they continue to evolve and circulate globally. H9N2 viruses are enzootic in most countries of the EMR. Although this virus does not cause a severe disease in poultry, it is considered a pathogen of high economic consequences especially in layer and breeder flocks.
AI risk assessment exercises must be routinely conducted on country and regional levels using available WHO tools and platforms with a multi-sectoral audience.
In the region, live bird markets and backyard poultry growing is common. Those production sectors tend to have low biosecurity measures and are likely the hotspots for AI activity. Enhancing biosecurity within those sectors and increasing awareness of market vendors and backyard growers may assist in mitigating the risk of AI.
Research further indicates that spill-over of H9N2 from poultry to humans occurs more frequently than what the surveillance systems detect and report. The burden of AI among exposed humans can be better understood through population-based studies at the humananimal interface that can capture mild or asymptomatic cases. Furthermore, the burden of AI among exposed humans can be better determined by enhancing surveillance for AI at the human-animal interface. This would be achieved by developing a region-wide plan to enhance surveillance for AI in poultry-exposed human populations and establishing systematic, active, and prospective AI animal surveillance programs focused on all HPAI and LPAI viruses. This should be complimented by increased event-based surveillance in the animal health sector with robust multi-disciplinary response to suspected AI outbreaks, including testing of exposed poultry-workers, tracing their contacts, and assessing their seroconversion.
A region-wide AI research agenda should be developed focused on epidemiological research and routes of transmission of AI across species. Regional training activities focused on designing and conducting AI research and surveillance should be provided. Enhancing laboratory capacity is also needed. Training on laboratory detection of AI (molecular and culture), serological detection of AI antibodies, and AI full-genome sequencing and analysis should be conducted by both animal and public health stakeholders. Moreover, it is of utmost importance to provide training on frameworks of adapting research findings into animal and public health policies.
A tripartite WHO/OIE/FAO program is required for the region to ensure that all implemented projects are conducted with the aim of improving countries' capacities to prevent, detect, and respond to AI. One Health paradigm needs to be operationalized and institutionalized to assure cross-sectoral communication, joint or linked surveillance systems, joint response activities, joint research activities, comprehensive national AI preparedness plans, and comprehensive national prevention, detection, and response policies.
This analysis revealed that AI research response remains weak in the EMR. To move forward, we recommend mapping and enhancing surveillance, research, and reporting capacities, improving surveillance at the human-animal interface, and working to operationalize and institutionalize the One Health paradigm for zoonotic influenza.